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1. The fast sodium inward current of freshly isolated single rat myocardial cells was studied by means of the internal perfusion‐voltage clamp method. 2. The voltage dependence of this current did not differ from the current‐voltage characteristics of the fast sodium inward current described for other excitable cells and tissues. 3. The time constant of inactivation of the Na+ current of the isolated myocardial cells ranged between 5.2 msec at ‐58 mV and 0.5 msec at +18 mV. The activation time constant ranged from 0.3 msec at ‐55 mV to 70 microseconds at +10 mV. 4. The reactivation time constant of the maximum sodium current at a holding potential of ‐100 mV was found to be 21 +/‐ 5 msec. 5. A mathematical model was developed for the simulation and analysis of the influence of the series and shunt resistances on the time response of the membrane potential. The results of the modelling make it clear that control of the series and shunt resistances in any given experiment is a conditio sine qua non for a valid analysis of the kinetic parameters of the sodium inward current. 6. Sodium currents with delayed activation kinetics must be regarded as an indication of insufficient control of the membrane potential.

Effects of ethmozine (moricizine) on the rapid inward sodium current (INa) were studied in freshly isolated single cells of rat ventricular myocardium. INawas measured by means of a patch clamp method for observing integral ionic currents. Ethmozine was applied extracellularly to a small cell membrane patch at concentrations of 10, 20, and 40 μM. At a stimulation frequency of 0.1 Hz the drug decreased the peak INawithout producing a shift of the current–voltage curve, but shifted the V0.5of the steady-state inactivation curve by −6 mV. At frequencies of 2–5 Hz the ethmozine-induced block exhibited a prominent use dependence, with trains of depolarizing clamp pulses 5–50 ms in duration eliciting maximal INafrom holding potentials at which the steady-state inactivation variable h∞ was close to 1. The use-dependent inhibition of INabecame more pronounced with an increase in both stimulation rate and pulse duration. In contrast to what has been observed in the node of Ranvier of the frog, the present results indicate that ethmozine binds to both inactivated and open Nachannels, but that the contribution of the open channel block to the overall block at depolarizing clamp step durations of several hundred milliseconds is small in comparison with the contribution of the block of inactivated channels.

The anticonvulsant activity of (+-)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benz am ide monohydrochloride (U-54494A), a benzamide derivative chemically related to kappa opioid receptor agonists, was investigated in three selected seizure models of experimental epilepsy. In the maximal electroshock seizure test in mice, U-54494A (ED50 28 mg/kg i.p.) was effective, with a potency somewhat less than phenobarbital. In combination with clinically used antiepileptics, especially phenobarbital and carbamazepine, the anticonvulsant activity of the latter was significantly increased. More detailed studies with phenobarbital showed additive anticonvulsant effects. The anticonvulsant activity of U-54494A was partially antagonized by naloxone. On the other hand, this compound did not elevate the pentylenetetrazol seizure threshold (at high doses a tendency of proconvulsant action was seen). Furthermore, in unrestrained rats with chronically implanted electrodes, U-54494A (> or = 10 mg/kg) significantly reduced the duration of electrically evoked hippocampal afterdischarges. However, the focal stimulation threshold was not markedly increased. With respect to the possible mode of action, whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes showed that U-54494A depressed the fast sodium inward current in a concentration- and frequency-dependent manner. In summary, our results agree with earlier reports that demonstrated marked anticonvulsant effects of U-54494A in grand mal-analogous seizure tests. Moreover, in combination with some standard antiepileptics, additive effects can be found. It is suggested that, in addition to kappa opioid and excitatory amino acid receptor related effects, modulations of Na+ membrane currents may contribute to the mechanisms of action.